Hydrochloric Acid → HCID 178480574, compound

Temperature

0 °C

A cold (0° C.) solution of tert-butyl 2-(4-fluorobenzyl)-2-[(8-benzyloxy-6-bromo-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)carbonyl]hydrazine-carboxylate (12.30 g, 20.45 mmol) in dichloromethane (150 mL) was saturated with anhydrous HCl gas. After stirring at 0° C. for half an hour, the mixture was treated with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous phase extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in benzene and concentrated under vacuum. The residual white solid was used without further purification. A solution of the above 8-(benzyloxy)-6-bromo-N-(4-fluorobenzyl)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carbohydrazide (5.20 g, 10.37 mmol) and dicyclohexylmethylamine (3.03 g, 15.53 mmol) in anhydrous DMF (100 mL) was purged with nitrogen for 10 minutes. Bis-(tri-tert-butylphosphine)palladium (0) (0.74 g, 1.45 mmol) was added and mixture was heated under an atmosphere of carbon monoxide (400 psi) in a stainless vessel in an oil bath at 90° C. overnight. The mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum to remove˜80 mL of the solvent. The residue was partitioned between dichloromethane (600 mL) and dilute aqueous HCl. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. As the solution was concentrated to about 20 mL, the solution was cooled in an ice-water bath. The solid precipitated was filtered, washed with cold (0° C.) dichloromethane, and dried in vacuum to provide the titled compound.

1. customThe organic layer was separated
2. extractionthe aqueous phase extracted with dichloromethane
3. washwashed with brine
4. dry with materialdried over anhydrous sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated under vacuum
7. dissolutionThe residue was dissolved in benzene
8. concentrationconcentrated under vacuum
9. customThe residual white solid was used without further purification
10. temperaturemixture was heated under an atmosphere of carbon monoxide (400 psi) in a stainless vessel in an oil bath at 90° C. overnight
11. filtrationThe mixture was filtered through a pad of Celite
12. concentrationThe filtrate was concentrated under vacuum
13. customto remove˜80 mL of the solvent
14. customThe residue was partitioned between dichloromethane (600 mL) and dilute aqueous HCl
15. extractionThe organic extract
16. washwas washed with brine
17. dry with materialdried over sodium sulfate
18. filtrationfiltered
19. concentrationconcentrated under vacuum
20. concentrationAs the solution was concentrated to about 20 mL
21. temperaturethe solution was cooled in an ice-water bath
22. customThe solid precipitated
23. filtrationwas filtered
24. washwashed with cold (0° C.) dichloromethane
25. customdried in vacuum

ORD record

ord-89b508e54d684288bb03156376db9289

Source dataset

uspto-grants-2009_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07538112B2